The aminoglycosides include streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others. They are used most widely in combination with other agents to treat drug-resistant organisms; for example, they are used with a β-lactam antibiotic in serious infections with Gram-negative bacteria, with a β-lactam antibiotic or vancomycin for Gram-positive endocarditis, and with one or more agents for treatment of mycobacterial infections, such as tuberculosis.
General Properties of Aminoglycosides
A. Physical and Chemical Properties
Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in other aminoglycosides), to which various amino sugars are attached by glycosidic linkages (Figures 45–1 and 45–2). They are water-soluble, stable in solution, and more active at alkaline than at acid pH.
Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other structures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. ➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁,➂,➃, and ➄; whereas plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.
The mode of action of streptomycin has been studied more closely than that of other aminoglycosides, but all aminoglycosides are thought to act similarly. Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is unclear. The initial event is passive diffusion via porin channels across the outer membrane (see Figure 43–3). Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process. The transmembrane electrochemical gradient supplies the energy for this process, and transport is coupled to a proton pump. Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient. Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of those antibiotics with aminoglycosides.
Inside the cell, aminoglycosides bind to 30S-subunit ribosomal proteins. Protein synthesis is inhibited by aminoglycosides in at least three ways (Figure 45–3): (1) interference with the initiation complex of peptide formation; (2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional protein; and (3) breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and leads to cell death.
Putative mechanisms of action of the aminoglycosides in bacteria. Normal protein synthesis is shown in the top panel. At least three aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called monosome. (Reproduced, with permission, from Trevor AT, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 6th ed. McGraw-Hill, 2002. Copyright © The McGraw-Hill Companies, Inc.)
C. Mechanisms of Resistance
Three principal mechanisms of resistance have been established: (1) production of a transferase enzyme that inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. This is the principal type of resistance encountered clinically. (2) There is impaired entry of aminoglycoside into the cell. This may result from mutation or deletion of a porin protein involved in transport and maintenance of the electrochemical gradient or from growth conditions under which the oxygen-dependent transport process is not functional. (3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.
D. Pharmacokinetics and Once-Daily Dosing
Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract, and almost the entire oral dose is excreted in feces after oral administration. However, the drugs may be absorbed if ulcerations are present. Aminoglycosides are usually administered intravenously as a 30–60 minute infusion. After intramuscular injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 30–90 minutes. After a brief distribution phase, peak serum concentrations are identical to those following intravenous injection. The normal half-life of aminoglycosides in serum is 2–3 hours, increasing to 24–48 hours in patients with significant impairment of renal function. Aminoglycosides are only partially and irregularly removed by hemodialysis—eg, 40–60% for gentamicin—and even less effectively by peritoneal dialysis. Aminoglycosides are highly polar compounds that do not enter cells readily. They are largely excluded from the central nervous system and the eye. In the presence of active inflammation, however, cerebrospinal fluid levels reach 20% of plasma levels, and, in neonatal meningitis, the levels may be higher. Intrathecal or intraventricular injection is required for high levels in cerebrospinal fluid. Even after parenteral administration, concentrations of aminoglycosides are not high in most tissues except the renal cortex. Concentration in most secretions is also modest; in the bile, the level may reach 30% of that in blood. With prolonged therapy, diffusion into pleural or synovial fluid may result in concentrations 50–90% of that of plasma.
Traditionally, aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function. However, administration of the entire daily dose in a single injection may be preferred in many clinical situations for at least two reasons. Aminoglycosides exhibit concentration-dependent killing; that is, higher concentrations kill a larger proportion of bacteria and kill at a more rapid rate. They also have a significant postantibiotic effect, such that the antibacterial activity persists beyond the time during which measurable drug is present. The postantibiotic effect of aminoglycosides can last several hours. Because of these properties, a given total amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses.
When administered with a cell wall-active antibiotic (a β-lactam or vancomycin), aminoglycosides may exhibit synergistic killing against certain bacteria. The effect of the drugs in combination is greater than the anticipated effect of each individual drug; ie, the killing effect of the combination is more than additive. This synergy may be important in certain clinical situations, such as endocarditis.
Adverse effects from aminoglycosides are both time- and concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is reached, but, once that concentration is achieved, the time beyond this threshold becomes critical. This threshold is not precisely defined, but a trough concentration above 2 mcg/mL is predictive of toxicity. At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose.
Numerous clinical studies demonstrate that a single daily dose of aminoglycoside is just as effective—and probably less toxic—than multiple smaller doses. Therefore, many authorities recommend that aminoglycosides be administered as a single daily dose in most clinical situations. However, the efficacy of once-daily aminoglycoside dosing in combination therapy of enterococcal and staphylococcal endocarditis in patients with a prosthetic valve remains to be defined, and administration of lower doses two or three times daily is still recommended. In contrast, limited data do support once-daily dosing in streptococcal endocarditis. The role of once-daily dosing in pregnancy, obesity, and in neonates also is not well defined.
Once-daily dosing has potential practical advantages. For example, repeated determinations of serum concentrations are unnecessary unless an aminoglycoside is given for more than 3 days. A drug administered once a day rather than three times a day is less labor intensive. And once-a-day dosing is more feasible for outpatient therapy.
Aminoglycosides are cleared by the kidney, and excretion is directly proportional to creatinine clearance. To avoid accumulation and toxic levels, once-daily dosing of aminoglycosides is generally avoided if renal function is impaired. Rapidly changing renal function, which may occur with acute kidney injury, must also be monitored to avoid overdosing or underdosing. Provided these pitfalls are avoided, once-daily aminoglycoside dosing is safe and effective. If the creatinine clearance is >60 mL/min, then a single daily dose of 5–7 mg/kg of gentamicin or tobramycin is recommended (15 mg/kg for amikacin). For patients with creatinine clearance <60 mL/min, traditional dosing as described below is recommended. With once-daily dosing, serum concentrations need not be routinely checked until the second or third day of therapy, depending on the stability of renal function and the anticipated duration of therapy. In most circumstances, it is unnecessary to check peak concentrations; an exception may be when ensuring adequately high peak concentrations for treating infections caused by drug-resistant pathogens. The goal is to administer drug so that concentrations of <1 mcg/mL are present between 18 and 24 hours after dosing. This provides sufficient time for washout of drug to occur before the next dose is given. Several nomograms have been developed and validated to assist clinicians with once-daily dosing (eg, Freeman reference).
With traditional dosing, adjustments must be made to prevent accumulation of drug and toxicity in patients with renal insufficiency. Either the dose of drug is kept constant and the interval between doses is increased, or the interval is kept constant and the dose is reduced. Nomograms and formulas have been constructed relating serum creatinine levels to adjustments in traditional treatment regimens. Because aminoglycoside clearance is directly proportional to the creatinine clearance, a method for determining the aminoglycoside dose is to estimate creatinine clearance using the Cockcroft-Gault formula described in Chapter 60. For a traditional twice- or thrice-daily dosing regimen, peak serum concentrations should be determined from a blood sample obtained 30–60 minutes after a dose, and trough concentrations from a sample obtained just before the next dose. Doses of gentamicin and tobramycin should be adjusted to maintain peak levels between 5 and 10 mcg/mL (typically between 8 and 10 mcg/mL in more serious infections) and trough levels <2 mcg/mL (<1 mcg/mL is optimal).
All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided if possible. Ototoxicity can manifest either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage with vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising serum creatinine levels or reduced creatinine clearance, although the earliest indication often is an increase in trough serum aminoglycoside concentrations. Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory damage. Streptomycin and gentamicin are the most vestibulotoxic. Neomycin, tobramycin, and gentamicin are the most nephrotoxic.
In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate, when given promptly, or neostigmine. Hypersensitivity occurs infrequently.
Aminoglycosides are mostly used against aerobic Gram-negative bacteria, especially when there is concern for drug-resistant pathogens or in critically ill patients. They are almost always used in combination with a β-lactam antibiotic to extend empiric coverage and to take advantage of the potential synergism between these two classes of drugs. Penicillin-aminoglycoside combinations have also been used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal endocarditis. Due to toxicity, these combinations are used less frequently when alternate regimens are available. For example, in the case of enterococcal endocarditis, studies suggest that the combination of ampicillin and ceftriaxone is an effective regimen with less risk for nephrotoxicity. When aminoglycosides are used, the selection of agent and dose depends on the infection being treated and the susceptibility of the isolate.
Streptomycin (Figure 45–1) was isolated from a strain of Streptomyces griseus. The antimicrobial activity of streptomycin is typical of that of other aminoglycosides, as are the mechanisms of resistance. Resistance has emerged in most species, restricting the current usefulness of streptomycin, with the exceptions listed below. Ribosomal resistance to streptomycin develops readily, limiting its role as a single agent.
A. Mycobacterial Infections
Streptomycin is mainly used as a second-line agent for treatment of tuberculosis. The dosage is 15 mg/kg/d with a maximum of 1 g/d (20–40 mg/kg/d for children), and it may be given intramuscularly or intravenously. It should be used only in combination with other agents to prevent emergence of resistance. See Chapter 47 for additional information regarding the use of streptomycin in mycobacterial infections.
B. Nontuberculous Infections
In plague, tularemia, and sometimes, brucellosis, streptomycin, 1 g twice daily (15 mg/kg twice daily for children), is given intramuscularly in combination with an oral tetracycline.
Penicillin plus streptomycin is effective for enterococcal endocarditis and 2-week therapy of viridans streptococcal endocarditis; however, for susceptible strains, gentamicin is used more commonly when an aminoglycoside is selected as adjunct therapy. Streptomycin remains a useful agent for treating gentamicin non-susceptible enterococcal infections, as some isolates that are resistant to gentamicin (and therefore resistant to netilmicin, tobramycin, and amikacin) will remain susceptible to streptomycin.
Fever, skin rashes, and other allergic manifestations may result from hypersensitivity to streptomycin. This occurs most frequently with a prolonged course of treatment (eg, for tuberculosis).
Pain at the injection site is common but usually not severe. The most serious toxic effect with streptomycin is disturbance of vestibular function—vertigo and loss of balance. The frequency and severity of this disturbance are in proportion to the age of the patient, the blood levels of the drug, and the duration of administration. Vestibular dysfunction may follow a few weeks of unusually high blood levels (eg, in individuals with impaired renal function) or months of relatively low blood levels. Vestibular toxicity tends to be irreversible. Streptomycin given during pregnancy can cause deafness in the newborn.
Gentamicin is a mixture of three closely related constituents, C1, C1A, and C2 (Figure 45–2) isolated from Micromonospora purpurea. It is effective against both Gram-positive and Gram-negative organisms, and many of its properties resemble those of other aminoglycosides.
Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many strains of staphylococci and Gram-negative bacteria, including P. aeruginosa and Enterobacteriaceae. Like all aminoglycosides, it has no activity against anaerobes.
Streptococci and enterococci are relatively resistant to gentamicin owing to failure of the drug to penetrate into the cell. However, gentamicin in combination with some penicillins or vancomycin produces a potent bactericidal effect, which in part is due to enhanced uptake of drug that occurs with inhibition of cell wall synthesis. Resistance to gentamicin rapidly emerges in staphylococci during monotherapy owing to selection of permeability mutants. Ribosomal resistance is rare. Among Gram-negative bacteria, resistance is most commonly due to plasmid-encoded aminoglycoside-modifying enzymes. Gram-negative bacteria that are gentamicin-resistant usually are susceptible to amikacin, which is much more resistant to modifying enzyme activity. The enterococcal enzyme that modifies gentamicin is a bifunctional enzyme that also inactivates amikacin, netilmicin, and tobramycin but not streptomycin; the latter is modified by a different enzyme. This is why some gentamicin-resistant enterococci are susceptible to streptomycin.
A. Intramuscular or Intravenous Administration
Gentamicin is used mainly in severe infections caused by Gram-negative bacteria that are likely to be resistant to other drugs, especially P aeruginosa, Enterobacter sp, Serratia marcescens, Proteus sp, Acinetobacter sp, and Klebsiella sp. It usually is used in combination with a second agent because an aminoglycoside alone may not be effective for infections outside the urinary tract. Aminoglycosides should not be used as single agents for therapy of pneumonia because penetration of infected lung tissue is poor and local conditions of low pH and low oxygen tension contribute to limited activity. Gentamicin 5–7 mg/kg/d traditionally is given intravenously in three equal doses, but once-daily administration is just as effective for some organisms and less toxic (see above).
Gentamicin, in combination with a cell wall-active antibiotic, may also be indicated in the treatment of endocarditis caused by Gram-positive bacteria (streptococci, staphylococci, and enterococci) as discussed earlier.
B. Topical and Ocular Administration
Creams, ointments, and solutions containing 0.1–0.3% gentamicin sulfate have been used for the treatment of infected burns, wounds, or skin lesions and in attempts to prevent intravenous catheter infections. The effectiveness of topical preparations for these indications is unclear. Topical gentamicin is partly inactivated by purulent exudates. Gentamicin can be injected intraocularly for treatment of certain eye infections.
C. Intrathecal Administration
Meningitis caused by Gram-negative bacteria has been treated by the intrathecal injection of gentamicin sulfate, 1–10 mg/d. However, neither intrathecal nor intraventricular gentamicin was beneficial in neonates with meningitis, and intraventricular gentamicin was toxic, raising questions about the usefulness of this form of therapy. Moreover, the availability of third-generation cephalosporins for Gram-negative meningitis has rendered this therapy obsolete in most cases. It may be used in cases of drug-resistant meningitis or severe β-lactam allergy.
Nephrotoxicity is usually reversible upon drug discontinuation. It occurs in 5–25% of patients receiving gentamicin for longer than 3–5 days. Such toxicity requires, at the very least, adjustment of the dosing regimen and should prompt reconsideration of the need for the drug, particularly if there is a less toxic alternative agent. Measurement of gentamicin serum levels is essential. Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular dysfunction. Loss of hearing can also occur. Ototoxicity is in part genetically determined, having been linked to point mutations in mitochondrial DNA, and occurs in 1–5% for patients receiving gentamicin for more than 5 days. Hypersensitivity reactions to gentamicin are uncommon.
This aminoglycoside (Figure 45–2) has an antibacterial spectrum similar to that of gentamicin. Although there is some cross-resistance between gentamicin and tobramycin, it is unpredictable in individual strains. Separate laboratory susceptibility tests are therefore necessary.
A. Intramuscular or Intravenous Administration
The pharmacokinetic properties of tobramycin are virtually identical with those of gentamicin. The daily dose of tobramycin is 5–7 mg/kg intramuscularly or intravenously, traditionally divided into three equal amounts and given every 8 hours but now often given as a single daily dose. Monitoring blood levels in renal insufficiency is an essential guide to proper dosing.
Tobramycin has almost the same antibacterial spectrum as gentamicin with a few exceptions. Gentamicin is slightly more active against S marcescens, whereas tobramycin is slightly more active against P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and tobramycin, but E faecium is resistant to tobramycin. Gentamicin and tobramycin are otherwise interchangeable clinically.
Like other aminoglycosides, tobramycin is ototoxic and nephrotoxic. Nephrotoxicity of tobramycin may be slightly less than that of gentamicin.
B. Inhaled and Ophthalmic Administration
Tobramycin is formulated in solution (300 mg in 5 mL) for inhalation for treatment of P aeruginosa lower respiratory tract infections complicating cystic fibrosis. The drug is recommended as a 300-mg dose regardless of the patient’s age or weight for administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days off therapy. Serum concentrations 1 hour after inhalation average 1 mcg/mL; consequently, nephrotoxicity and ototoxicity rarely occur. Caution should be used when administering tobramycin to patients with preexisting renal, vestibular, or hearing disorders. Tobramycin is also available as 0.3% ophthalmic ointment and drops for the treatment of superficial eye infections. These formulations result in minimal systemic absorption and are unlikely to cause systemic adverse effects.
Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule (Figure 45–2). It is resistant to many enzymes that inactivate gentamicin and tobramycin, and, therefore, can be used against some microorganisms resistant to the latter drugs. Many Gram-negative bacteria, including many strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are inhibited by 1–20 mcg/mL amikacin in vitro. After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly, peak levels in serum are 10–30 mcg/mL.
Strains of multidrug-resistant Mycobacterium tuberculosis, including streptomycin-resistant strains, are usually susceptible to amikacin. Kanamycin-resistant strains may be cross-resistant to amikacin. The dosage of amikacin for tuberculosis is 10–15 mg/kg/d as a once-daily or two to three times weekly injection and always in combination with other drugs to which the isolate is susceptible.
Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Serum concentrations should be monitored. Target peak serum concentrations for an every-12-hours dosing regimen are 20–40 mcg/mL, and trough levels should be maintained between 4 and 8 mcg/mL.
Netilmicin shares many characteristics with gentamicin and tobramycin. However, the addition of an ethyl group to the 1-amino position of the 2-deoxystreptamine ring (ring II, Figure 45–2) sterically protects the netilmicin molecule from enzymatic degradation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions. Consequently, netilmicin may be active against some gentamicin-resistant and tobramycin-resistant bacteria.
The dosage (5–7 mg/kg/d) and the routes of administration are the same as for gentamicin. Netilmicin is largely interchangeable with gentamicin or tobramycin but is no longer available in the United States.
Neomycin, kanamycin, and paromomycin have similar pharmacologic properties.
Antimicrobial Activity & Resistance
Drugs of the neomycin group are active against Gram-positive and Gram-negative bacteria and some mycobacteria. P aeruginosa and streptococci are generally resistant. Mechanisms of antibacterial action and resistance are the same as with other aminoglycosides. The former widespread use of these drugs in bowel preparation for elective surgery contributed to the selection of resistant organisms and some outbreaks of enterocolitis in hospitals. Cross-resistance between kanamycin and neomycin is complete and may result in amikacin cross-resistance.
Like all aminoglycosides, drugs of the neomycin group are poorly absorbed from the gastrointestinal tract. After oral administration, the intestinal flora is suppressed or modified, and the drug is excreted in the feces. Excretion of any absorbed drug is mainly through glomerular filtration into the urine.
Neomycin is generally limited to topical and oral use due to toxicity associated with parenteral use and higher resistance rates compared to other aminoglycosides. Kanamycin use is limited to treatment of multi-drug-resistant tuberculosis, although alternate agents, such as amikacin, may be preferred. It is no longer available in the USA. Paromomycin has been shown to be effective against visceral leishmaniasis when given parenterally (see Chapter 52), and this serious infection may represent an important use for this drug. Paromomycin can be used for intestinal Entamoeba histolytica infection and is sometimes used for intestinal infections with other parasites.
A. Topical Administration
Solutions containing 1–5 mg/mL neomycin have been used on infected surfaces or injected into joints, the pleural cavity, tissue spaces, or abscess cavities where infection is present. The total amount of drug given in this fashion must be limited to 15 mg/kg/d because at higher doses enough drug may be absorbed to produce systemic toxicity. Whether topical application for active infection adds anything to appropriate systemic therapy is questionable. Ointments, often formulated as a neomycin-polymyxin-bacitracin combination, can be applied to infected skin lesions or in the nares for suppression of staphylococci but they are largely ineffective.
In preparation for elective bowel surgery, 1 g of neomycin may be given orally every 6–8 hours for 1–2 days, often combined with 1 g of erythromycin base. This reduces the aerobic bowel flora with little effect on anaerobes. In hepatic encephalopathy, coliform flora can be suppressed by giving 1 g every 6–8 hours together with reduced protein intake, thus reducing ammonia production. Use of neomycin for hepatic encephalopathy has been largely supplanted by lactulose and other medications that are less toxic. Use of paromomycin in the treatment of protozoal infections is discussed in Chapter 52.
C. Intravenous and Intramuscular Administration
When used intravenously, the standard dose for kanamycin is 15 mg/kg/day in two to three divided doses, whereas for treatment of tuberculosis, 15 mg/kg is usually given intramuscularly as a single daily dose. In the case of once daily administration, kanamycin peak concentrations are typically between 35 and 45 mcg/mL, while trough concentrations should be undetectable.
All members of the neomycin group have significant nephrotoxicity and ototoxicity. Auditory function is affected more than vestibular function. Deafness may occur, especially in adults with impaired renal function and prolonged elevation of drug levels.
The sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3–5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest. Calcium gluconate and neostigmine can act as antidotes.
Although hypersensitivity is not common, prolonged application of neomycin-containing ointments to skin and eyes has resulted in severe allergic reactions.
Plazomicin is a new aminoglycoside under development and is expected to undergo review by the U.S. Food and Drug Administration in 2017. It has been studied in phase II clinical trials for treatment of urinary tract infections; phase III clinical trials are underway for treatment of carbapenem-resistant Enterobacteriaceae. It is a synthetic molecule derived from sisomicin, an aminoglycoside no longer available,. Various structural modifications have yielded a compound less susceptible to most aminoglycoside modifying enzymes, thus retaining activity against aminoglycoside-resistant pathogens. It appears to have similarly potent in vitro activity against Enterobacteriaceae and displays two- to four-fold lower MICs against nonfermenting Gram-negative bacilli (eg, P aeruginosa) when compared with gentamicin, tobramycin, and amikacin. It has activity similar to gentamicin against staphylococci. A 15-mg/kg dose yields mean peak and trough concentrations of 113 mcg/mL and 0.43 mcg/mL, respectively. The half-life is about 4 hours, and it is being studied as a single daily dose. Due to limited clinical experience, it is unclear whether the toxicity profile will be similar to other aminoglycosides; however, no ototoxicity or nephrotoxicity has been observed in early trials.